Study Findings Explain Why Chemotherapy May be Compromised in Patients With Pancreatic Cancer

A study may explain why chemotherapy drugs such as gemcitabine are not effective for many patients with pancreatic cancer, and perhaps point to new approaches to treatment including enhancing gemcitabine's ability to stop tumor growth. The study, done in mice, was published in Nature (doi:10.1038/nature16064).

The study suggests that suppressing a cellular plasticity process known as epithelial-to-mesenchymal transition (EMT) in combination with gemcitabine, may boost the drug's effectiveness.

“Diagnosis of pancreatic cancer is associated with poor prognosis despite the availability of current therapies,” said lead author Raghu Kalluri, MD, PhD, professor and chair of Cancer Biology at The University of Texas MD Anderson Cancer Center in Houston. “Therefore new treatment strategies are urgently needed.”

Kalluri's team looked at EMT, an embryonic cellular plasticity program that is hijacked by cancer cells and is thought to help cancer cells migrate to other organs. Cancer cells spread disease by either dividing (proliferation), or by migrating, allowing them to metastasize. When cancer cells adopt an EMT program to promote their migration, they generally stop dividing. The research findings indicate that EMT leads to arrest of cancer cell proliferation causing impaired sensitivity to chemotherapy, impacting the body's ability to effectively respond to such treatment.

“Gemcitabine works primarily on cancer cells that are dividing or proliferating,” said Kalluri. “When cancer cells suspend their proliferation, such as when they launch an EMT program, then antiproliferation drugs like gemcitabine do not target them well.”

“We found that EMT program suppressed drug transporter and concentrative proteins, which inadvertently protected these cancer cells from antiproliferative drugs such as gemcitabine,” added Kalluri. “The correlation of decreased survival of pancreatic cancer patients with an increased EMT program is likely due to their impaired capacity to respond to chemotherapy, leading to overall poor prognosis and higher incidence of metastasis.”

Inhibiting EMT program led to enhanced response of tumors to gemcitabine.

“Collectively, our study offers the opportunity to evaluate the potential of targeting EMT program to enhance efficacy of chemotherapy and likely targeted therapies,” said Kalluri.

Funding for this study was from the Cancer Prevention and Research Institute of Texas.